Mast cells are major effector cells in the pathogenesis of asthma. Insights into novel mechanisms that regulate IgE signals can lead to therapeutic targets for asthma and allergic diseases. MicroRNAs (miRNAs) are small, non-coding RNAs that negatively regulate protein expression by binding and inhibiting mRNA targets;they have been implicated as key regulators in a number of normal and pathologic processes. While specific miRNAs that mediate inflammatory responses have been identified, the role that miRNAs play in mediating IgE- dependent mast cell responses is unexplored. This proposal will test the hypothesis that miRNAs modulate IgE-mediated responses by regulating key inflammatory mediators from mast cells. We have performed an array screen for miRNAs regulated by IgE signaling;we found widespread repression of miRNAs, including let-7 miRNAs. Specific aim #1 will investigate miRNA regulation of IgE activation by examining mast cells globally depleted of miRNAs by genetic targeting and RNAi approaches. In specific aim #2, we will determine whether the let-7 miRNAs regulate the expression of IL-13, an interleukin that promotes airway inflammation and responsiveness. In specific aim #3, we will use mice with mast cells either globally depleted of miRNAs or overexpressing let-7 in a murine model of asthma. We will use this system to examine the role of IgE-regulated miRNAs in the development of airway inflammation and responsiveness. The goal of this pilot study will be to establish the miRNA regulatory network in IgE activated mast cells. The insights gained from this project may lead to new and innovative strategies for the treatment of asthma. PUBLIC HEALTH RELEVANCE: The pilot proposal will examine the hypothesis that mast cell microRNAs are important regulators of airway inflammation and reactivity. There is an emerging paradigm that microRNAs play a role in fine-tuning immune responses;however, their function in mediating mast cell activation is unexplored. These studies may provide insights into novel mechanisms that regulate IgE function and lead to therapeutic strategies for asthma.